RU2733376C2 - Improved method of producing osimertinib (azd9291) or its salt and "aniline-azd9291" or its salt - Google Patents

Abstract

FIELD: pharmaceuticals.SUBSTANCE: invention relates to a method of producing a compound of formula (II) or a pharmaceutically acceptable salt thereof, which comprises: a) reacting a compound of formula (III) or a salt thereof with hydrogen in the presence of a catalyst based on palladium (0) and/or platinum (0) and in the presence of an acid to form a compound of formula (I) or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; b) reacting the obtained compound of formula (I) or a salt thereof with an activated derivative or precursor of acrylic acid and, if necessary, treatment with a base to form a compound of formula (II) and c) optionally forming a pharmaceutically acceptable salt thereof. Invention also relates to a method of producing a compound of formula (I) or a salt thereof.(I)(III).EFFECT: novel method of producing a compound of formula (II) with high output.19 cl, 2 tbl, 22 ex

Description

Osimertinib (also known as " AZD9291 ") is a compound that is used in clinical trials of certain types of cancer, in particular certain types of non-small cell lung cancer (NSCLC). It can be used in the form of the free base or as a pharmaceutically acceptable salt thereof, such as, for example, the mesylate salt. The present invention relates to an improved chemical process for the preparation of a compound of formula (I) or a salt thereof,

(I).

The compound of formula (I) or a salt thereof is useful as an intermediate in the late steps of the preparation of osimertinib and the preparation of the pharmaceutically acceptable salts of osimertinib. The compound of formula (I) is referred to herein as " aniline-AZD9291 " and may also be known by its chemical name: N ¹ - (2-dimethylaminoethyl) -5-methoxy- N ¹ -methyl- N ⁴ - [4- (1 -methylindol-3-yl) pyrimidin-2-yl] benzene-1,2,4-triamine.

The chemical structure of osimertinib (also known as " AZD9291 ") is shown below as formula (II) :

(II).

International Patent Publication No. WO 2013/014448 discloses AZD9291 and pharmaceutically acceptable salts of AZD9291. It also discloses that AZD9291 can be prepared by reacting aniline-AZD9291 with an activated acrylic acid derivative or precursor (e.g. acryloyl chloride), preferably in the presence of a suitable base (e.g., a trialkylamine base) as shown in Scheme 1 below.

Scheme 1

WO2013 / 014448 also discloses that AZD9291 can be prepared from aniline-AZD9291 by reacting with 3-chloropropanoyl chloride. In one example, sodium hydroxide is used as the base. In another example, potassium carbonate and triethylamine are used as bases to prepare AZD9291 as shown in Scheme 2 below.

Scheme 2

WO 2013/014448 also describes a process for preparing aniline-AZD9291 from a compound of formula (III) , as shown in Scheme 3 below.

Scheme 3

The compound of formula (III) is referred to herein as " nitrodiamine-AZD9291 " and may be known by its chemical name: N ¹ - [2- (dimethylamino) ethyl] -5-methoxy- N ¹ -methyl- N ⁴ - [4- (1-methylindol-3-yl) pyrimidin-2-yl] -2-nitrobenzene-1,4-diamine.

The method described in WO 2013/014448 (shown in Scheme 3 above) uses iron as a reducing agent. One of ordinary skill in the art will appreciate that iron-based residues such as iron oxide will be present in the reaction mixture, and that removal of such residues can be practically difficult, especially on a large scale, for example, as part of any method for making AZD9291 ( or a pharmaceutically acceptable salt thereof). Additional processing steps may be necessary to remove significant amounts of iron residues on an industrial scale.

Alternatively, the present inventors have now found that aniline AZD9291 can be produced by reducing nitrodiamine-AZD9291 by hydrogenating nitrodiamine-AZD9291 in the presence of a palladium-carbon catalyst or a platinum-carbon catalyst. However, when choosing a platinum-carbon-based catalyst, the present inventors were surprised to find that a problematic impurity can be generated when nitrodiamine-AZD9291 is hydrogenated to aniline-AZD9291. The present inventors have identified the structure of the hindering impurity, and its chemical structure is shown as formula (IV) below:

(Iv).

The compound of formula (IV) is referred to herein as " hydroxyaniline-AZD9291 " and may also be known by its chemical name: [2-amino-5-methoxy-4- (4- (1-methylindol-3-yl) pyrimidine-2 -ylamino) phenol]. The inventors have also discovered that hydroxyaniline-AZD9291 can lead to the formation of additional degradation products in the synthesis of aniline-AZD9291. Removal of these unwanted impurities in the aggregate can be difficult, and one or more of the impurities are dark colored. As a result of careful chemical research, conditions were ultimately found to ensure the removal of impurities in the subsequent processing carried out by the present inventors, but it would obviously be preferable to avoid / minimize the initial formation of such impurities, if possible.

It will be understood that the levels of impurities in the pharmaceutical product and pharmaceutical intermediates at a later stage need to be controlled to a suitable safe level. For all pharmaceutical products, it is important to establish a manufacturing method that is sufficiently robust and optimized to ensure a pre-determined high quality substance is obtained. At the same time, the process needs to be suitable for large-scale production to provide sufficient AZD9291 (or a pharmaceutically acceptable salt thereof) to meet global demand.

The present inventors have surprisingly discovered an improved process for the preparation of aniline-AZD9291 (or a salt thereof). The improved process results in an improved impurity composition of aniline-AZD9291, where, according to the analysis of the present inventors, absolutely no formation of the hydroxyaniline-AZD9291 impurity is detected. In turn, the absence of hydroxyaniline-AZD9291 leads to a decrease in the likelihood of the formation of further decomposition products. Aniline-AZD9291 obtained by the improved method can be further processed to produce AZD9291 or a pharmaceutically acceptable salt of AZD9291, for example AZD9291 mesylate. This improved method is characterized by the ability to reduce the risk of a failed batch, increase the reaction yield and, as a result, increase the overall yield of AZD9291 (or its pharmaceutically acceptable salt). This can provide a cost and / or time advantage as fewer batches of a substance may need to be processed or disposed of.

Accordingly, there is provided an improved method for preparing AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction nitrodiamine-AZD9291 of the formula (III) or a salt thereof,

with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid to form aniline-AZD9291 of formula (I) or a salt thereof,

(I),

where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or a salt thereof with an activated acrylic acid derivative or precursor and, if necessary, treating it with a base to form AZD9291 of formula (II) :

; и

; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutically acceptable salt of AZD9291 is a mesylate salt.

One of ordinary skill in the art will understand that the inclusion of acid addition in the process for making aniline-AZD9291 in the presence of water (or in the presence of a mixture of water and a water-miscible solvent) will promote the formation of an impurity such as hydroxyaniline-AZD9291 due to the presence of water (which can act as a reactant) and the presence of an acid (which can act as a catalyst for hydrolysis). However, contrary to such expectations, the present inventors have surprisingly found that the inclusion of acid addition in the process for making aniline-AZD9291 actually results in significantly lower levels of hydrolysis product (hydroxyaniline-AZD9291) obtained. Indeed, in the examples described later in this document, hydroxyaniline-AZD9291 is not detected using standard analytical methods known to the present inventors.

Thus, it will be understood that the process of the present invention results in significant manufacturing advantages, for example: (1) less risk of a failed batch due to improved impurity composition; (2) easier post-processing to obtain AZD9291 (or a pharmaceutically acceptable salt thereof) of sufficient purity for pharmaceutical use; (3) the possibility of increasing the reaction yield to obtain aniline-AZD9291 and, therefore, AZD9291; and (4) the possibility of simplifying the process for producing aniline-AZD9291 itself.

Stage a)

It will be understood that palladium (0) catalysts and platinum (0) catalysts may be provided on activated carbon. It should be understood that the amount of catalyst present in the reaction mixture is generally expressed herein as the molar amount of platinum and / or palladium metals present in the catalyst (s), but not as the total weight of the catalyst present (which may, for example , include moisture and any support such as activated carbon, etc.), and the amount of catalyst, when "molar equivalents" are mentioned, is a ratio to the amount of nitrodiamine-AZD9291 used in the reaction. Consequently, expressing the amount of catalyst present as the amount of platinum and / or palladium takes into account variations in the noble metal content of the catalyst, which can vary due to reasons such as noble metal loading, the amount of supported activated carbon, and the water content of the catalyst.

Accordingly, the catalyst is a palladium (0) and / or platinum (0) catalyst.

In one embodiment, the palladium (0) and / or platinum (0) catalyst contains at least 0.0005 molar equivalents of palladium (0).

In one embodiment, the palladium (0) and / or platinum (0) catalyst contains at least 0.001 molar equivalents of palladium (0).

In one embodiment, the palladium (0) and / or platinum (0) catalyst contains at least 0.005 molar equivalents of palladium (0).

In one embodiment, the palladium (0) and / or platinum (0) catalyst contains at least 0.0001 molar equivalents of platinum (0).

In one embodiment, the palladium (0) and / or platinum (0) catalyst contains at least 0.0002 molar equivalents of platinum (0).

In one embodiment, the palladium (0) and / or platinum (0) catalyst contains at least 0.001 molar equivalents of platinum (0).

In one embodiment, the palladium (0) and / or platinum (0) catalyst is based on activated carbon.

In one embodiment, the palladium (0) and / or platinum (0) catalyst comprises a palladium (0) catalyst.

In one embodiment, the palladium (0) catalyst contains one or more additional metals in addition to palladium (0).

In a further embodiment, the metal in the palladium (0) catalyst is predominantly palladium (0).

In one embodiment, the palladium (0) and / or platinum (0) catalyst is a palladium (0) catalyst.

In one embodiment, the palladium (0) catalyst contains at least 0.0005 molar equivalents of palladium (0).

In another embodiment, the palladium (0) catalyst contains at least 0.001 molar equivalents of palladium (0).

In another embodiment, the palladium (0) catalyst contains at least 0.005 molar equivalents of palladium (0).

In a further embodiment, the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0).

In one embodiment, the palladium (0) and / or platinum (0) catalyst comprises a platinum (0) catalyst.

In another embodiment, the platinum (0) catalyst contains one or more additional metals in addition to platinum (0).

In another embodiment, the metal in the platinum (0) catalyst is predominantly platinum (0).

In one embodiment, the palladium (0) and / or platinum (0) catalyst is a platinum (0) catalyst.

In one embodiment, the platinum (0) catalyst contains at least 0.0001 molar equivalents of platinum (0).

In another embodiment, the platinum (0) catalyst contains at least 0.0002 molar equivalents of platinum (0).

In another embodiment, the platinum (0) catalyst contains at least 0.001 molar equivalents of platinum (0).

In a further embodiment, the platinum (0) catalyst contains 0.001 molar equivalent of platinum (0).

In one aspect, one or more additional transition metals such as vanadium may be present in the catalyst along with platinum and / or palladium, for example, there may be a mixture of platinum and vanadium in a weight ratio of at least 1: 1, such as 1: 2. In this aspect, the platinum (0) or palladium (0) present in the catalyst is believed to be the metal that is predominantly responsible for catalyzing the reaction.

In one embodiment:

the palladium (0) -based activated carbon catalyst contains at least 0.0001 molar equivalents of palladium (0);

the platinum (0) based catalyst on activated carbon contains at least 0.0005 molar equivalent of platinum (0); or

a catalyst based on platinum (0) and vanadium on activated carbon, where the weight ratio of platinum (0) to vanadium in the catalyst is 1: 2, contains at least 0.0005 molar equivalent of platinum (0).

Accordingly, the reaction of nitrodiamine-AZD9291 (or a salt thereof) to form aniline-AZD9291 (or a salt thereof) is carried out in the presence of an acid.

Suitable acids are Bronsted acids, for example carboxylic acids, sulfonic acids and mineral acids, which are miscible with and / or soluble in water or a mixture of water and a water miscible solvent.

In one embodiment, the acid is Bronsted acid.

In one embodiment, the acid is a Bronsted acid that is miscible with and / or soluble in water or a mixture of water and a water miscible solvent.

In one embodiment, the acid comprises an acid selected from carboxylic acid, sulfonic acid, and mineral acid.

In one embodiment, the acid provides an acid selected from a carboxylic acid, a sulfonic acid, and a mineral acid that is miscible with and / or soluble in water or a mixture of water and a water miscible solvent.

In one embodiment, the acid comprises a carboxylic acid.

In one embodiment, the acid provides a carboxylic acid that is miscible with and / or soluble in water or a mixture of water and a water miscible solvent.

In one embodiment, the acid comprises sulfonic acid.

In one embodiment, the acid provides a sulfonic acid that is miscible with and / or soluble in water or a mixture of water and a water miscible solvent.

In another embodiment, the acid comprises a mineral acid.

In another embodiment, the acid provides a mineral acid that is miscible with and / or soluble in water or a mixture of water and a water miscible solvent.

In one embodiment, the carboxylic acid provides an acid selected from (C _1-7 hydrocarbyl) -COOH, formic acid, trichloroacetic acid, and trifluoroacetic acid. An example of (C ₃ hydrocarbyl) -COOH is n- butanoic acid. An example of (C ₆ hydrocarbyl) -COOH is benzoic acid.

In another embodiment, the carboxylic acid comprises an acid selected from acetic acid and trifluoroacetic acid.

In another embodiment, the sulfonic acid provides an acid selected from methanesulfonic acid, benzenesulfonic acid, and p- toluenesulfonic acid.

In another embodiment, the sulfonic acid provides an acid selected from methanesulfonic acid and benzenesulfonic acid.

In another embodiment, the mineral acid provides an acid selected from hydrochloric acid, sulfuric acid, and phosphoric acid.

In another embodiment, the acid comprises an acid selected from (C _1-7 hydrocarbyl) -COOH, formic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid.

In another embodiment, the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid.

In one embodiment, the acid comprises (C _1-7 hydrocarbyl) -COOH.

In one embodiment, the acid comprises acetic acid.

In one embodiment, the acid comprises formic acid.

In one embodiment, the acid comprises trichloroacetic acid.

In one embodiment, the acid comprises trifluoroacetic acid.

In one embodiment, the acid comprises methanesulfonic acid.

In one embodiment, the acid comprises benzenesulfonic acid.

In one embodiment, the acid comprises p- toluenesulfonic acid.

In one embodiment, the acid comprises hydrochloric acid.

In one embodiment, the acid comprises sulfuric acid.

In one embodiment, the acid comprises phosphoric acid.

In one embodiment, the acid is (C _1-7 hydrocarbyl) -COOH.

In one embodiment, the acid is acetic acid.

In one embodiment, the acid is formic acid.

In one embodiment, the acid is trichloroacetic acid.

In one embodiment, the acid is trifluoroacetic acid.

In one embodiment, the acid is methanesulfonic acid.

In one embodiment, the acid is benzenesulfonic acid.

In one embodiment, the acid is p- toluenesulfonic acid.

In one embodiment, the acid is hydrochloric acid.

In one embodiment, the acid is sulfuric acid.

In one embodiment, the acid is phosphoric acid.

In a further aspect, at least 1.0 molar equivalent of the acid is used. In one embodiment, 1.0-2.0 molar equivalents of acid are used. In another embodiment, 1.4-1.6 molar equivalents of acid are used. In a further embodiment, 1.6 molar equivalents of acid are used. For convenience, 1.5 molar equivalents of acid are used. It should be understood that the amount (molar equivalents) of acid added is in relation to the amount of nitrodiamine-AZD9291.

Accordingly, the reaction of nitrodiamine-AZD9291 (or its salt) to form aniline-AZD9291 (or its salt) is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent. If it is stated that "the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent", it should be understood that said water, in part, in whole or in no way, may come from the acid used in the reaction (if the acid that used, contains some water, for example, hydrochloric acid).

In one embodiment, the reaction is carried out in the presence of water.

In one embodiment, the reaction is carried out in water.

In another embodiment, the reaction is carried out in the presence of a mixture of water and a water miscible solvent.

In additional embodiments, the water miscible solvent is selected from alcohol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and N- methylpyrrolidin-2-one.

In an embodiment, the water miscible solvent is selected from alcohol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, and N- methylpyrrolidin-2-one.

In another embodiment, the water miscible solvent is selected from (C _1-6 alkyl) -OH, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and N- methylpyrrolidin-2-one.

An example of (C ₃ alkyl) -OH is isopropanol. An example of (C ₅ alkyl) -OH is cyclopentanol.

In a further embodiment, the water miscible solvent is selected from methanol, ethanol, propanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and N- methylpyrrolidin-2-one. In another embodiment, the water miscible solvent is selected from methanol, ethanol, n- propanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and N- methylpyrrolidin-2-one. In a further embodiment, the water miscible solvent is selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, and N- methylpyrrolidin-2-one.

In one embodiment, the water miscible solvent comprises (C _1-6 alkyl) —OH.

In one embodiment, the water miscible solvent comprises methanol.

In one embodiment, the water miscible solvent comprises ethanol.

In one embodiment, the water miscible solvent comprises propanol.

In one embodiment, the water miscible solvent comprises n-propanol.

In one embodiment, the water miscible solvent comprises isopropanol.

In one embodiment, the water miscible solvent comprises tetrahydrofuran.

In one embodiment, the water miscible solvent comprises acetonitrile.

In one embodiment, the water miscible solvent comprises dimethyl sulfoxide.

In one embodiment, the water miscible solvent comprises dimethylformamide.

In one embodiment, the water miscible solvent comprises dimethylacetamide.

In one embodiment, the water miscible solvent comprises N- methylpyrrolidin-2-one.

In one embodiment, the water miscible solvent is (C _1-6 alkyl) —OH.

In one embodiment, the water miscible solvent is methanol.

In one embodiment, the water miscible solvent is ethanol.

In one embodiment, the water miscible solvent is propanol.

In one embodiment, the water miscible solvent is n-propanol.

In one embodiment, the water miscible solvent is isopropanol.

In one embodiment, the water miscible solvent is tetrahydrofuran.

In one embodiment, the water miscible solvent is acetonitrile.

In one embodiment, the water miscible solvent is dimethyl sulfoxide.

In one embodiment, the water miscible solvent is dimethylformamide.

In one embodiment, the water miscible solvent is dimethylacetamide.

In one embodiment, the water miscible solvent is N- methylpyrrolidin-2-one.

Additional suitable conditions are described in the examples in this document.

It will be understood that a mixture of water and a water miscible solvent will imply that the mixture may include more than one water miscible solvent.

In one embodiment, a mixture of water and a water miscible solvent is described herein with the proviso that the water miscible solvent does not include a ketone solvent such as acetone.

The reactions with hydrogen described herein are preferably carried out at a pressure> 0.2 bar, for example 0.2-10 bar. Accordingly, in one embodiment, the reaction with hydrogen is carried out at a pressure greater than 0.2 bar. In a further embodiment, the reaction with hydrogen is carried out at a pressure in the range of 0.2 to 10 bar. In a further embodiment, the reaction with hydrogen is carried out at a pressure of 2.5 to 3.5 bar, for example 3 bar.

The reactions with hydrogen described herein are preferably carried out at pressures> 0.2 barg, for example 0.2-10 barg. Accordingly, in one embodiment, the reaction with hydrogen is carried out at a pressure greater than 0.2 barg. In a further embodiment, the reaction with hydrogen is carried out at a pressure in the range of 0.2 to 10 barg. In a further embodiment, the reaction with hydrogen is carried out at a pressure of 1.5 to 2.5 barg, for example 2 barg.

The reactions with hydrogen described herein are preferably carried out at temperatures> 0 ° C, for example 0-70 ° C. Accordingly, in one embodiment, the reaction with hydrogen is carried out at a temperature greater than 0 ° C. In an additional embodiment, the reaction with hydrogen is carried out at a temperature ranging from 0 ° C to 70 ° C. In a further embodiment, the reaction with hydrogen is carried out at a temperature in the range of 40 to 60 ° C, for example 45 to 55 ° C, for example 50 ° C.

Stage b)

Specific examples of suitable "activated derivatives or precursors of acrylic acid" are

analogs of acryloyl halide or 3-halopropanoyl, where the halide is chloride or bromide, and where the halogen is chlorine or bromine. Alternative activated acrylic acid derivatives or precursors that can provide the desired acryloyl functionality are known in the art. Such alternatives may include, for example, variants of acryloyl halide or 3-halopropanoyl halide, where an alternative leaving group is used in place of the halide. Other techniques can use, for example, acrylic acid, but use conditions under which acryloyl halide is formed in-situ in the reaction mixture. Similarly, 3-chloropropanoic acid or acrylic acid can be used together with an amide binder. Techniques for coupling carboxylic acids to amino groups are well known in the art.

Consequently, in one embodiment, the activated acrylic acid derivative or precursor is selected from acryloyl halide and 3-halopropanoyl halide (where each halide and halogen is independently selected from chlorine and bromine); or selected from 3-chloropropanoic acid and acrylic acid if conditions for coupling amides are used.

Accordingly, in one embodiment, the activated acrylic acid derivative or precursor is selected from acryloyl halide and 3-halopropanoyl halide (wherein each halide and halogen is independently selected from chlorine and bromine); or selected from 3-chloropropanoic acid and acrylic acid if an amide binder is used.

Thus, in one embodiment, the activated acrylic acid derivative or precursor is selected from acryloyl halide and 3-halopropanoyl halide, where halide and halogen are each independently selected from chlorine and bromine.

In one embodiment, the activated acrylic acid derivative or precursor is acryloyl chloride or 3-chloropropanoyl chloride.

In one embodiment, the activated acrylic acid derivative or precursor is acryloyl chloride.

In another embodiment, the activated acrylic acid derivative or precursor is 3-chloropropanoyl chloride.

In one aspect, the resulting aniline-AZD9291 (or a salt thereof) is reacted with an activated acrylic acid derivative or precursor and, if necessary, treated with a base to form AZD9291 (or a pharmaceutically acceptable salt thereof). In one embodiment, the resulting aniline-AZD9291 (or a salt thereof) is reacted with an activated acrylic acid derivative or precursor and treated with a base to form AZD9291 (or a pharmaceutically acceptable salt thereof). In one aspect, there is provided for reacting the resulting aniline-AZD9291 (or a salt thereof) with analogs of acryloyl halide or 3-halopropanoyl (wherein the halide is chloride or bromide, and where halogen is chlorine or bromine) and, if necessary, treatment with a base to form AZD9291 (or a pharmaceutically acceptable salt thereof). In one embodiment, it is contemplated to react the resulting aniline-AZD9291 (or a salt thereof) with an acryloyl halide or 3-halopropanoyl halide (wherein the halide is chloride or bromide, and where the halogen is chlorine or bromine) and treating with a base to form AZD9291 (or pharmaceutically acceptable salt). In a further embodiment, the resulting aniline-AZD9291 (or a salt thereof) is reacted with acryloyl chloride or 3-chloropropanoyl chloride and treated with a base to form AZD9291 (or a pharmaceutically acceptable salt thereof). In another embodiment, the resulting aniline-AZD9291 (or a salt thereof) is reacted with an activated acrylic acid derivative or precursor. In one embodiment, there is provided a reaction of the resulting aniline-AZD9291 (or a salt thereof) with an acryloyl halide or 3-halopropanoyl halide (wherein the halide is chloride or bromide, and where the halogen is chlorine or bromine). In a further embodiment, the resulting aniline-AZD9291 (or a salt thereof) is reacted with acryloyl chloride or 3-chloropropanoyl chloride. One of ordinary skill in the art will appreciate that, depending on the type of activated acrylic acid derivative or precursor used, it may not necessarily be necessary to treat with a base to form AZD9291. A person skilled in the art will understand that if treatment with a base is necessary, then the base can be added to the reaction mixture at the same time as other reagents, for example, at the same time as aniline-AZD9291 (or a salt thereof) and an activated derivative or precursor of acrylic acid; or at another point in the reaction sequence.

Stage c)

Suitable pharmaceutically acceptable salts are acid addition salts such as an acid addition salt formed using an inorganic acid or an organic acid. In one embodiment, the acid addition salt may be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. In another embodiment, an acid addition salt may be formed using an organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and p- toluenesulfonic acid. In one embodiment, the pharmaceutically acceptable salt is a mesylate salt.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides an acid selected from carboxylic acid, sulfonic acid and mineral acid, with the formation of aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides an acid selected from (C _1-7 hydrocarbyl) -COOH, formic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) and / or platinum (0) catalyst and in the presence of at least 1.0 molar equivalent of an acid, wherein the acid is an acid selected from acetic acid , trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of 1.0-2.0 molar equivalent of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of 1.4-1.6 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of 1.6 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid , methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of 1.5 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid , methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains at least 0.0005 molar equivalent palladium (0), and the platinum (0) catalyst (if present) contains at least 0.0001 molar equivalents of platinum (0), and in the presence of at least 1 molar acid equivalent to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

d) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) and / or platinum (0) catalyst, where the palladium (0) catalyst (if present) contains at least 0.005 molar equivalent of palladium ( 0), and the platinum (0) catalyst (if present) contains at least 0.001 molar equivalent of platinum (0), and in the presence of at least 1 molar equivalent of acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

e) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

f) optional formation of a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0) and in the presence of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst and in the presence of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) based catalyst and in the presence of at least 1.0 molar equivalent of an acid, where the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and in the presence of 1.0-2.0 molar equivalent of acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid , benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and in the presence of 1.4-1.6 molar equivalents of acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid , benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) -based catalyst and in the presence of 1.6 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst and in the presence of 1.5 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid , hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum (0) -based catalyst and in the presence of at least 1.0 molar equivalent of an acid, where the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on platinum (0) and in the presence of 1.0-2.0 molar equivalent of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid , benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on platinum (0) and in the presence of 1.4-1.6 molar equivalents of acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid , benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0) and in the presence of 1.6 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0) and in the presence of 1.5 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of at least 1.0 molar equivalent of an acid, where the acid provides methanesulfonic acid, to form aniline -AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum (0) catalyst and in the presence of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst and in the presence of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or its salt, where the reaction carried out in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of at least 1.0 molar equivalent of an acid, where the acid provides methanesulfonic acid, to form aniline -AZD9291 or its salts, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of at least 1.0 molar equivalent of an acid, where the acid provides methanesulfonic acid, to form aniline -AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of a mixture of water and a water-miscible solvent, where the water-miscible solvent is selected from alcohol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidin-2-one;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent, where the water-miscible solvent is selected from (C _1-6 alkyl ) -OH, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide and N- methylpyrrolidin-2-one;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of at least 1.0 molar equivalent of an acid, where the acid provides methanesulfonic acid, to form aniline -AZD9291 or its salts, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent, where the water-miscible solvent is selected from (C _1-6 alkyl) -OH, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide and N- methylpyrrolidine - 2-she;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of at least 1.0 molar equivalent of an acid, where the acid provides methanesulfonic acid, to form aniline -AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent, where the water-miscible solvent is selected from methanol, ethanol, propanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide and N- methylpyrrolidin-2-one;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of at least 1.0 molar equivalent of an acid, where the acid provides methanesulfonic acid, to form aniline -AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of a mixture of water and a water-miscible solvent, wherein the water-miscible solvent is selected from methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide and N- methylphenol 2-she;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of at least 1.0 molar equivalent of an acid, where the acid provides methanesulfonic acid, to form aniline -AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of a mixture of water and a water-miscible solvent, wherein the water-miscible solvent is selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidin-2-one;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or its salt, where the reaction carried out in the presence of water;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of at least 1.0 molar equivalent of an acid, where the acid provides methanesulfonic acid, to form aniline -AZD9291 or its salts, where the reaction is carried out in the presence of water;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of 1.4-1.6 molar equivalents of an acid, where the acid is selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of water;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of 1.4-1.6 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of 1.4-1.6 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent, where the water-miscible solvent is selected from methanol , isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, and N- methylpyrrolidin-2-one;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides an improved method for making AZD9291, or a pharmaceutically acceptable salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), or a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, where the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence in the presence of a mixture of water and a water-miscible solvent, where the water-miscible solvent is selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidin-2-one;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optionally forming a pharmaceutically acceptable salt thereof.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on platinum (0) and in the presence of 1.4-1.6 molar equivalents of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum (0) catalyst and in the presence of 1.5 molar equivalents of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum (0) catalyst and in the presence of 1.6 molar equivalents of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains at least 0.0001 molar equivalents of platinum (0), and in the presence of an acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains 0.001 molar equivalent of platinum (0), and in the presence of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains 0.001 molar equivalent of platinum (0), and in the presence of 1.5 molar equivalents of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains 0.001 molar equivalent of platinum (0), and in the presence of 1.5 molar equivalents of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains 0.001 molar equivalent of platinum (0), and in the presence of 1.5 molar equivalents of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains 0.001 molar equivalent of platinum (0), and in the presence of 1.5 molar equivalents of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent, where the water-miscible solvent is selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidine-2- she;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.6 molar equivalents of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.6 molar equivalents of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.6 molar equivalents of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.6 molar equivalents of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water miscible solvent, where the water miscible solvent is selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N - methylpyrrolidin-2-one;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and in the presence of 1.4-1.6 molar equivalents of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and in the presence of 1.5 molar equivalents of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and in the presence of 1.6 molar equivalents of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains at least 0.0005 molar equivalent of a palladium (0) catalyst, and in the presence of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0), and in the presence of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0), and in the presence of 1.5 molar equivalent of an acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0), and in the presence of 1.5 molar equivalent of an acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water;

b) reacting the obtained aniline-AZD9291 or its salt with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0), and in the presence of 1.5 molar equivalent of an acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of a mixture of water and a water-miscible solvent;

b) reacting the resulting aniline-AZD9291 with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0), and in the presence of 1.5 molar equivalent of an acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent, where the water-miscible solvent is selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidine-2- she;

b) reacting the resulting aniline-AZD9291 with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0), and in the presence of 1.6 molar equivalent of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent;

b) reacting the resulting aniline-AZD9291 with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0), and in the presence of 1.6 molar equivalent of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water;

b) reacting the resulting aniline-AZD9291 with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0), and in the presence of 1.6 molar equivalent of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of a mixture of water and a water-miscible solvent;

b) reacting the resulting aniline-AZD9291 with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

In a further aspect of the present invention, there is provided an improved method for making AZD9291, or a mesylate salt thereof, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0), and in the presence of 1.6 molar equivalent of acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent, where the water-miscible solvent is selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidine-2- she;

b) reacting the resulting aniline-AZD9291 with acryloyl chloride or 3-chloropropanoyl chloride and, if necessary, treating with a base to form AZD9291; and

c) optional mesylate salt formation.

From the above aspects, it will be understood that the molar equivalents of the reagents used are expressed relative to the molar amount of nitrodiamine-AZD9291 used, i.e., by default, it is assumed that 1.0 molar equivalent of nitrodiamine-AZD9291 is used.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of water or in the presence a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides an acid selected from carboxylic acid, sulfonic acid and mineral acid, with the formation of aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides an acid selected from (C _1-7 hydrocarbyl) -COOH, formic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) and / or platinum (0) catalyst and in the presence of at least 1.0 molar equivalent of an acid, wherein the acid is an acid selected from acetic acid , trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) and / or platinum (0) catalyst and in the presence of at least 1.0 molar equivalent of an acid, wherein the acid is an acid selected from acetic acid , trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent, where the water-miscible solvent selected from (C _1-6 alkyl) -OH, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide and N- methylpyrrolidin-2-one; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of 1.0-2.0 molar equivalent of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of 1.4-1.6 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and 1.6 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of 1.5 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid , methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) -based catalyst and in the presence of 1.5 molar equivalents of an acid, where the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains at least 0.0005 molar equivalent of palladium (0), and in the presence of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and miscible with solvent water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains at least 0.0005 molar equivalent of palladium (0), and in the presence of 1.5 molar equivalent of acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains at least 0.005 molar equivalents of palladium (0), and in the presence of 1.5 molar equivalents acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium (0) catalyst, where the palladium (0) catalyst contains 0.005 molar equivalent of palladium (0), and in the presence of 1.5 molar equivalent of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and miscible with solvent water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0) and in the presence of 1.5 molar equivalents of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains at least 0.0001 molar equivalent of platinum (0), and in the presence of 1.5 molar equivalent of acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid or phosphoric acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on platinum (0), where the catalyst based on platinum (0) contains at least 0.001 molar equivalent of platinum (0), and in the presence of 1.5 molar equivalent acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid, or phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains at least 0.001 molar equivalent of platinum (0), and in the presence of an acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent ; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a platinum-based catalyst (0), where the platinum-based catalyst (0) contains 0.001 molar equivalent of platinum (0), and in the presence of 1.5 molar equivalents of acid, where the acid provides an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water or in the presence of a mixture of water and miscible with solvent water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of at least 1.0 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of at least 1.4-1.6 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid , methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.6 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and the platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of at least 1.0 molar equivalents of acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and the platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of at least 1.4-1.6 molar equivalents of an acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or its salts, where the reaction is carried out in the presence of water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.6 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of water; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) reacting nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a palladium-based catalyst (0) or a platinum-based catalyst (0) and in the presence of an acid, where the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from alcohol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidin-2-one; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, with the formation of aniline-AZD9291 or its salt, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from (C _1-6 alkyl) -OH, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide , dimethylacetamide and N- methylpyrrolidin-2-one; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, to form aniline-AZD9291 or a salt thereof, wherein the reaction is carried out in the presence of a mixture of water and water-miscible solvent selected from methanol, ethanol, propanol, tetrahydrofuran, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide and N -methylpyrrolidin-2-one; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide , dimethylacetamide and N- methylpyrrolidin-2-one; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of at least 1.0 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolide 2-she; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidin-2-one ; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.6 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, to form aniline-AZD9291 or its salt, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidin-2-one ; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.4-1.6 molar equivalents of an acid, wherein the acid comprises an acid selected from acetic acid, trifluoroacetic acid, methanesulfonic acid , benzenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolide -2-she; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and the platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of at least 1.0 molar equivalents of acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidin-2-one; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.5 molar equivalents of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or N- methylpyrrolidin-2-one; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.6 molar equivalents of an acid, where the acid provides methanesulfonic acid, to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidin-2-one; and

b) optional filtration of the resulting mixture.

In a further aspect of the present invention, an improved process for the formation of aniline-AZD9291 or a salt thereof is provided, which comprises:

a) carrying out the reaction of nitrodiamine-AZD9291 or its salt with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0), where the catalyst based on palladium (0) (if present) contains 0.005 molar equivalent of palladium (0), and a platinum (0) catalyst (if present) contains 0.001 molar equivalents of platinum (0), and in the presence of 1.4-1.6 molar equivalents of an acid, where the acid provides methanesulfonic acid to form aniline-AZD9291 or a salt thereof, where the reaction is carried out in the presence of a mixture of water and a water-miscible solvent selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N- methylpyrrolidin-2-one; and

b) optional filtration of the resulting mixture.

From the above aspects, it will be understood that the molar equivalents of the reagents used are expressed in relation to the amount of nitrodiamine-AZD9291 used, i.e., by default, it is assumed that 1.0 molar equivalent of nitrodiamine-AZD9291 is used.

In a further aspect of the present invention, there is provided compound AZD9291, or a pharmaceutically acceptable salt thereof, prepared by steps a) to c) of the method described herein.

In a further aspect of the present invention, there is provided an aniline-AZD9291 compound, or a salt thereof, obtained by step a) of the method described in any aspect or embodiment or claims disclosed herein.

In another aspect of the present invention, there is provided a method for preparing aniline-AZD9291 or a salt thereof, which comprises step a) of the method described in any aspect, embodiment, or claims disclosed herein.

In an additional aspect of the present invention, there is provided a pharmaceutical composition comprising the AZD9291 compound, or a pharmaceutically acceptable salt thereof, prepared by process steps a) to c) described in any aspect, embodiment, or claims disclosed herein.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising the AZD9291 compound, or a pharmaceutically acceptable salt thereof, prepared by process steps a) to c) described in any aspect, embodiment or claims disclosed herein, together with one or several pharmaceutically acceptable diluents, carriers or excipients.

Thus, in a further aspect of the present invention, a product is provided that can be obtained by the method described by any aspect, embodiment, or claims of the present invention.

In another aspect of the present invention, there is provided a product obtained by the method described by any aspect, embodiment, or claims of the present invention.

One or more aspects, embodiments, and claims disclosed herein may be combined together to provide additional aspects, embodiments, and claims in all combinations except where the context suggests that the combination is clearly inappropriate. / inappropriate.

Abbreviations

Bar hut pressure in bar above atmospheric pressure.

Lb / sq. inch h. gauge pressure in pounds per square inch.

The present invention is further illustrated by the following examples.

Example 1

Nitrodiamine-AZD9291 (10.0 g), 5% platinum on activated carbon (0.001 molar equivalent, humidity 50%, 0.2 g, relative weight 0.02), methanesulfonic acid (3.23 g, 1.6 molar equivalent) and water (100 ml, 10 relative volumes) in a sealed autoclave. An inert atmosphere was created at the top of the vessel by 5 cycles of nitrogen injection. The mixture was warmed to 50 ° C and the top of the vessel was purged with 3 cycles of hydrogen injection. The mixture was stirred for 4 hours at 50 ° C with the introduction of hydrogen gas to maintain the pressure at the top of the vessel at 2 barg. The vessel was inert with nitrogen purge cycles and filtered to remove catalyst particles. The pure filtrates were mixed with 2-methyltetrahydrofuran (60 ml, 6 relative volumes) and 2 M sodium hydroxide in water (19 ml, 1.8 mol. Equiv.). After mixing for some time, the mixture was precipitated and the lower aqueous layer was discarded. The organic layers were washed once with water (80 ml, 8 relative volumes) and then diluted with 2-methyltetrahydrofuran (80 ml, 8 relative volumes). A solution of the product in 2-methyltetrahydrofuran was distilled at 50 ° C. under reduced pressure to give a residual volume of 60 ml. Aniline-AZD9291 (seed) was added and the mixture was cooled to 0 ° C for 4 hours. The resulting slurry was filtered and the collected solids washed with 2-methyltetrahydrofuran (20 ml, 2 vol) to give aniline-AZD9291 as an off-white powder (7.0 g, 75% yield) after drying under vacuum. In the obtained aniline-AZD9291, no hydroxyaniline-AZD9291 content was detected by UPLC.

UPLC technique

Equipment: High performance liquid chromatograph equipped with

UV detector. The system must be able to provide linear

gradient.

Column: UPLC BEH, phenyl, 1.7 μm, 2.1 x 100 mm, or equivalent

Phase A : 0.06% v / v trifluoroacetic acid in water Phase B : 0.06% v / v trifluoroacetic acid in acetonitrile Gradient profile ¹ : Time (minutes)
0.0
13 20
22 Phase A
90
85
thirty
90 Phase B
ten
fifteen
70
ten Consumption : 0.6 ml min ^-1 Administration volume : 1 μl Column temperature : 45 ° C Sample temperature : 5 ° C Wavelength : 245 nm Sample concentration : 1.0 mg / ml (approx) Diluent : 40/60 / 0.1 v / v MeCN / water / trifluoroacetic acid

Example 2

The following illustrates the general synthesis of aniline-AZD9291, where the aqueous acid solution, catalyst and solvent system were varied. Table 1 shows the names of these variables used and their quantities, where appropriate. Table 2 shows the results of HPLC analysis for aniline-AZD9291, synthesized according to the procedure indicated below.

General synthesis of aniline-AZD9291

Nitrodiamine-AZD9291 (290 to 310 mg), catalyst (variable type, variable amounts), solvent (10 relative volumes, 3.0 ml) and acid (variable type, 1.5 molar equivalents) were added to the Biotage Endeavor glass liner. The liner was placed in an Endeavor hydrogenation unit and the unit was sealed. The manifold was purged with nitrogen. The vessel was purged by flushing with nitrogen three times (up to 4 barg, without stirring). The manifold was purged with hydrogen. The program was launched with the instruction:

heating up to 50 ° C;

stirring at 300 rpm for 10 minutes;

charge hydrogen to a total pressure at the top of the vessel of 44 psi. psig, resulting in a total hydrogen partial pressure of 44 psig. inch.

stirring at 1000 rpm, maintaining hydrogen pressure, monitoring the absorption rate.

The reaction was stopped after 3-4 hours in a hydrogen atmosphere. The block was opened to communicate with the atmosphere. The reaction mixture was filtered through a 0.45 μm hydrophilic syringe filter (Millipore LHM) to remove catalyst residues. The filtrate was collected for analysis by HPLC (1 drop in 1.5 ml 75: 25: 0.1 (v / v / v) MeCN / water / trifluoroacetic acid).

HPLC technique

Equipment : Liquid chromatograph equipped with a UV detector. The system must be able to provide a linear gradient. Column : 30 x 4.6mm, XBridge BEH, C18, 1.7um (Waters) or equivalent Gradient profile ¹ : Time (minutes)
0.0
5.2
5.7
5.8 Water content
95
ten
ten
95 Acetonitrile content
five
90
90
five Ammonium acetate (w / v%)
0.01
0.01
0.01
0.01 Data collection time : 6.2 minutes Total analysis time : 8.5 min including equilibration Consumption : 2.0 ml min ^-1 Administration volume : 5 μl Column temperature : 40 ° C Wavelength : 225 nm

Experiment Acid Solvent Catalyst-metal type Catalyst (manufacturer's information) The amount of added catalyst (molar equivalents) ^{1, 2} End time of introduction (hours) AND Methanesulfonic acid Water Platinum / Vanadium CF1082 BV / W (1% Pt + 2% V / C) (Evonik) 0.001 ³ 1.5 B Methanesulfonic acid Water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 1.4 C Methanesulfonic acid Water Palladium Type 490 (10% Pd / C)
(Johnson Matthey) 0.005 3.3 D Methanesulfonic acid Water Ruthenium Type 97 (5% Ru / C)
(Johnson Matthey) 0.005 Lack of response or very slow response E Methanesulfonic acid Water Rhodium Type 592 (5% Rh / C)
(Johnson Matthey) 0.005 1.3 F Methanesulfonic acid 80:20 v / v
Methanol / water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 0.7 G Methanesulfonic acid 80:20 v / v
Isopropanol /
water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 0,4 H Methanesulfonic acid 80:20 v / v
Tetrahydrofuran / water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 1.0 J Methanesulfonic acid 80:20 v / v
Acetone / water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 1.0 K Methanesulfonic acid 80:20 v / v
Acetonitrile /
water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 1.1 L ⁵ Methanesulfonic acid 80:20 v / v
Dimethyl Sulfoxide /
water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 > 4 M Methanesulfonic acid 80:20 v / v
N-methylpyrrolidinone /
water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 2.0 N Acetic acid Water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 1.3 P Trifluoroacetic acid Water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 1.0 Q Benzenesulfonic acid Water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 2.0 R Hydrochloric acid Water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 2.6 S Sulfuric acid ⁴ Water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 1.6 T Phosphoric acid Water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.001 1.8 U ⁵ Methanesulfonic acid 80:20 v / v
Dimethyl Sulfoxide /
water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.0025 Not fixed-siro-vano V Trifluoroacetic acid 80:20 v / v
Tetrahydrofuran / water Platinum Type 18 (5% Pt / C)
(Johnson Matthey) 0.0005 See note ⁶ W Sulfuric acid ⁴ 80:20 v / v
N-methylpyrrolidinone /
water Palladium Type 490 (10% Pd / C) (Johnson Matthey) 0.01 Not fixed-siro-vano X Acetic acid 80:20 v / v
Acetonitrile /
water Palladium Type 490 (10% Pd / C)
(Johnson Matthey) 0.005 Not fixed-siro-vano

Table 1. Names of acid, solvent and catalyst used and amounts of acid and catalyst used in the synthesis of aniline-AZD9291 illustrated in example 2.

¹ With respect to nitrodiamine-AZD9291.

^{2 The} amount of catalyst added refers to the amount of noble metal added to the reaction mixture, not the amount of catalyst.

³ Catalyst loading in relation to the amount of platinum in the catalyst.

⁴ For reactions using sulfuric acid, the load was 0.75 mol. eq. since sulfuric acid is dibasic and the second pKa (2) is acidic enough to have the same effect as the first.

⁵ Reaction L was repeated (see Reaction U) with a higher catalyst loading (0.0025 mol. Equiv. Versus 0.001 mol. Equiv.) To ensure complete conversion.

⁶This experiment was much slower than expected, so after completion of reactions N, P, Q, R, S and T, which were carried out simultaneously with reaction V, and after sampling for analysis by HPLC, more catalyst was added (16 mg, 0.003 mol. eq.) into reaction V and the reaction was carried out again. A sample was taken from reaction V after an additional 60 minutes under the same conditions, after which the reaction ended.

% ¹ areas of analysis by HPLC Experiment Aniline-AZD9291 Nitrodiamine-AZD9291 Hydroxyaniline-AZD9291 AND 98.67 n. about. n. about. B 98.47 n. about. n. about. C 98.54 n. about. 0.16 D ² There is no data There is no data There is no data E 97.37 n. about. 0.76 F 98.99 n. about. n. about. G 99.17 n. about. n. about. H 99.23 n. about. n. about. J ³ 96.36 n. about. n. about. K 98.73 0.43 n. about. L 78.10 20.59 n. about. M 98.89 n. about. n. about. N 99,00 n. about. n. about. P 98.94 n. about. n. about. Q 99.14 n. about. n. about. R 99.21 n. about. n. about. S 98.91 n. about. n. about. T 98.98 n. about. n. about. U 98.67 n. about. n. about. V 98.93 n. about. n. about. W 96.68 n. about. 0.10 X 94,00 4.93 n. about.

Table 2. HPLC analysis of aniline-AZD9291 synthesized according to example 2

¹ ND = not detected. The estimated detection limit of the method is <0.1% of the area

² No reaction or very slow reaction was observed in this experiment. HPLC data not available.

³ In this experiment, no detectable amounts of hydroxyaniline-AZD9291 were observed, but other impurities were observed due to the presence of acetone in the reaction mixture. The range of total other impurities was defined as 2.91% area.

Claims (32)

1. A method of obtaining a compound of formula (II)

or a pharmaceutically acceptable salt thereof, which includes: a) carrying out the reaction of a compound of formula (III) or a salt thereof,

with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid to form a compound of formula (I) or a salt thereof,

(I), where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent; b) reacting the resulting compound of formula (I) or a salt thereof with an activated acrylic acid derivative or precursor and, if necessary, treating with a base to form a compound of formula (II), and c) optionally forming a pharmaceutically acceptable salt thereof. 2. A process for the preparation of a compound of formula (I) or a salt thereof, which comprises reacting a compound of formula (III) or a salt thereof,

with hydrogen in the presence of a catalyst based on palladium (0) and / or platinum (0) and in the presence of an acid to form a compound of formula (I) or a salt thereof,

(I), where the reaction is carried out in the presence of water or in the presence of a mixture of water and a water-miscible solvent. 3. A method according to any of the preceding claims, wherein the acid comprises an acid selected from carboxylic acid, sulfonic acid, and mineral acid. 4. The method of claim 3, wherein the carboxylic acid comprises an acid selected from (C _1-7 hydrocarbyl) -COOH, formic acid, trichloroacetic acid, and trifluoroacetic acid. 5. The method of claim 3, wherein the sulfonic acid comprises an acid selected from methanesulfonic acid, benzenesulfonic acid, and p- toluenesulfonic acid. 6. The method of claim 3, wherein the mineral acid comprises an acid selected from hydrochloric acid, sulfuric acid, and phosphoric acid. 7. A method according to any one of the preceding claims, wherein at least 1.0 molar equivalent of acid is used. 8. A process according to any of the preceding claims, wherein 1.0-2.0 molar equivalents of acid are used. 9. The method according to any of the preceding claims, wherein 1.5 molar equivalents of acid are used. 10. A process according to any one of the preceding claims, wherein the palladium (0) and / or platinum (0) catalyst comprises a palladium (0) catalyst. 11. A process according to any of the preceding claims, wherein the palladium (0) and / or platinum (0) catalyst contains at least 0.0005 molar equivalents of palladium (0). 12. A process according to any of the preceding claims, wherein the palladium (0) and / or platinum (0) catalyst comprises a platinum (0) catalyst. 13. A process according to any of the preceding claims, wherein the palladium (0) and / or platinum (0) catalyst contains at least 0.0001 molar equivalents of platinum (0). 14. A process according to any one of the preceding claims, wherein the water miscible solvent is selected from alcohol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidin-2-one. 15. A process according to any one of the preceding claims, wherein the water miscible solvent is selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, and N-methylpyrrolidin-2-one. 16. The method according to any one of claims. 1-13, wherein the reaction of a compound of formula (III) or a salt thereof is carried out in the presence of water. 17. The method according to claim 1 or any of claims. 3-16, wherein the activated acrylic acid derivative or precursor is acryloyl chloride or 3-chloropropanoyl chloride. 18. The method according to claim 1 or any of claims. 3-17, wherein the activated acrylic acid derivative or precursor is acryloyl chloride. 19. The method according to claim 1 or any of claims. 3-17, wherein the activated acrylic acid derivative or precursor is 3-chloropropanoyl chloride.